Questioning the Role of Carotid Artery Ultrasound in Assessing Fluid Responsiveness in Critical Illness: A Systematic Review and Meta-Analysis

Background A noninvasive and accurate method of identifying fluid responsiveness in hemodynamically unstable patients has long been sought by physicians. Carotid ultrasound (US) is one such modality previously canvassed for this purpose. The aim of this novel systematic review and meta-analysis is to investigate whether critically unwell patients who are requiring intravenous (IV) fluid resuscitation (fluid responders) can be identified accurately with carotid US. Methods The protocol was registered with PROSPERO on the 30/11/2022 (ID number: CRD42022380284). Studies investigating carotid ultrasound accuracy in assessing fluid responsiveness in hemodynamically unstable patients were included. Studies were identified through searches of six databases, all run on 4 November 2022, Medline, Embase, Emcare, APA PsycInfo, CINAHL, and Cochrane Library. Risk of bias was assessed using the QUADAS-2 and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines. Results were pooled, meta-analysis was conducted where amenable, and hierarchical summary receiver operating characteristic models were established to compare carotid ultrasound measures. Results Seventeen studies were included (n = 842), with 1048 fluid challenges. 441 (42.1%) were fluid responsive. Four different carotid US measures were investigated, including change in carotid doppler peak velocity (∆CDPV), carotid blood flow (CBF), change in carotid artery velocity time integral (∆CAVTI), and carotid flow time (CFT). Pooled carotid US had a pooled sensitivity, specificity, and AUROC with 95% confidence intervals (CI) of 0.73 (0.66–0.78), 0.82 (0.72–0.90), and 0.81 (0.78–0.85), respectively. ∆CDPV had sensitivity, specificity, and AUROC with 95% CI of 0.72 (0.64–0.80), 0.87 (0.73–0.94), and 0.82 (0.78–0.85), respectively. CBF had sensitivity, specificity, and AUROC with 95% CI of 0.70 (0.56–0.80), 0.80 (0.50–0.94), and 0.77 (0.78–0.85), respectively. Risk of bias and assessment was undertaken using the QUADAS-2 and GRADE tools. The QUADAS-2 found that studies generally had an unclear or high risk of bias but with low applicability concerns. The GRADE assessment showed that ∆CDPV and CBF had low accuracy for sensitivity and specificity. Conclusion It appears that carotid US has a limited ability to predict fluid responsiveness in critically unwell patients. ∆CDPV demonstrates the greatest accuracy of all measures analyzed. Further high-quality studies using consistent study design would help confirm this.


Introduction
Intravenous fuid administration is the frst-line therapy for patients presenting with acute circulatory failure [1].While early fuid resuscitation reverses organ hypoperfusion and improves clinical outcomes, inappropriate fuids can increase morbidity and mortality [2][3][4].A "fuid responder" is a patient who, upon receiving an intravenous fuid bolus, incurs an increase to their cardiac output.Tese patients are said to have "preload reserve," where increasing their cardiac preload improves their stroke volume (SV) and ultimately cardiac output (CO).A "fuid nonresponder" is a patient whose stroke volume will not improve with further fuids, refecting either an already optimised preload or advanced disease state.Reliable noninvasive and readily available tools to identify fuid responders in the setting of acute resuscitation remain clinically challenging as accurate and timely assessment of the fuid status requires either invasive or technically difcult procedures [5][6][7].
Ultrasound has had an increasingly important role in assessing fuid responsiveness in critically unwell patients in both emergency departments and intensive care units.Tere has been recent interest in the diagnostic accuracy of carotid artery ultrasound (US) as a noninvasive, accessible way to assess fuid responsiveness [8].Te seminal work conducted by Marik et al. [9] showed that carotid artery velocity time integral (CAVTI) had 94% sensitivity and 86% specifcity in detecting fuid responsiveness in septic patients.Several studies have attempted to replicate the fndings of this study in diferent clinical areas; however, heterogenous populations with small sample sizes make it difcult to draw meaningful conclusions.
Prior systematic review and meta-analyses of carotid ultrasound in determining fuid responsiveness have yielded promising results.Yao et al. [10] and Singla et al. [11] found that carotid US could be used to determine fuid responsiveness in surgical and ventilated patients.Similarly, Beier et al. [12] found that carotid US was a valid measure of fuid responsiveness in both healthy and unwell patients.Critically unwell patients have not been investigated in isolation.Patients in physiological extremis cannot be compared to elective and semielective surgical patients.Tese patients often require more intensive treatments, have longer stays in ICU, and have higher mortality rates than surgical patients [13,14].Te aim of this novel systematic review and meta-analysis is to investigate whether critically unwell patients who are requiring intravenous (IV) fuid resuscitation (fuid responders) can be identifed accurately with carotid US.

Methods
Tis review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis of Diagnostic Test Accuracy (PRISMA-DTA) statement [15].Te protocol was registered with PROSPERO on the 30/11/ 2022 (ID number: CRD42022380284).

Study Selection and Inclusion
Criteria.Studies were selected according to the PICOS statement.

Patients and Setting.
All studies which investigated the utility of carotid ultrasound as a measure of fuid responsiveness in critically unwell patients (shock of any kind and vasopressor requirement) were considered.Critically unwell was determined as patients who were requiring resuscitation as a result of some pathological process.Surgical studies were excluded unless they fulflled this criterion independently of their surgery, e.g., appendicitis with septic shock.Studies were excluded if they had a portion of the cohort that was critically unwell, and the data were pooled and could not be separated.To avoid further confounding all noncritically ill subjects, healthy volunteers and children were also excluded.

Index Tests and Reference Standards.
Studies needed to have a reference standard for fuid responsiveness which was compared to a carotid ultrasound measure.Reference standards were any independent measure of measuring cardiac output or equivalent, e.g., cardiac index and stroke volume.Studies that investigated carotid US but had no reference standard were excluded.

Comparison and Reference Standard.
Reference standards were any independent measure of measuring cardiac output or equivalent, e.g., cardiac index and stroke volume.Studies that investigated carotid US but had no reference standard were excluded.

Outcome and Target Condition.
Te target condition was fuid responsiveness.Tis was determined by measuring the reference standard before and after a fuid challenge.A fuid challenge could be achieved by providing the patient with a bolus of intravenous fuid or by providing them an "autotransfusion" by performing a passive leg raise (PLR).Patients were deemed fuid responsive if their cardiac output increased by a predetermined threshold.Studies which did not include an assessment of fuid responsiveness were excluded.
Te primary outcome was the predictive value of carotid ultrasound measures to determine fuid responsiveness, expressed as an area under the receiver operating characteristics curve (AUROC).Studies which did not include AUROC, sensitivity, and specifcity or studies in which these values could not be calculated were excluded.

Study Design and Report Characteristics.
Only prospective studies were included.Animal studies were excluded, as were the following publication types: books, chapters, conference abstracts, comments, dissertations, editorials, guidelines, letters, news, notes, policy statements, and study protocols.Papers in languages other than English were excluded.Final search strategies combined the general concepts of ultrasonography AND carotid velocity time integral AND fuid responsiveness using a combination of subject headings and text words.An initial search was developed for Ovid Medline and then adapted for other databases adjusting subject headings and syntax as appropriate (Figure 1).Search syntax used in the Ovid databases was adapted for CINAHL (EBSCOhost) and Cochrane (Wiley) using the Polyglot Search Translator [17].Trial registries were searched using the strategy "ultrasound AND carotid AND fuid."

Study Selection.
Database search results were exported to EndNote bibliographic management software (Clarivate Ltd, U.S.) and duplicates removed.In accordance with eligibility criteria records, these were screened on the publication type by HW within EndNote and book sections, comments, dissertations, and letters were excluded.All remaining records were loaded into Covidence systematic review software (Veritas Health Innovation Ltd) for screening on title and abstract.Records were independently screened on title and abstract in Covidence by two reviewers, SW and AL, and conficts were resolved by HA.Full text records were retrieved for the remaining records.

Data Collection, Management, and Defnitions.
Data from all relevant studies were collected in the following domains: (1) study characteristics including author, year of publish, mean age, setting, sampling, percentage of fuid responders, percentage mechanically ventilated, type of fuid challenge, reference standard and threshold, carotid measure, and equipment used; (2) diagnostic performance, including sensitivity, specifcity, true positives (TPs), true negatives (TNs), false positives (FPs) and false negatives (FNs), and AUROC and 95% confdence interval (CI).Where studies performed more than one carotid measure or more than one cohort of fuid challenges, these results were independently used for their relevant analysis.A true positive was defned as a signifcant change in carotid US measure in response to a fuid challenge as well a positive change in cardiac output or equivalent as per the predetermined reference standard.A true negative was deemed a nonresponder by the reference standard and a nonsignifcant carotid US measure.A false positive was considered diagnosis of fuid responsive for the carotid US measure that was not confrmed by the reference standard.A false negative was considered not a fuid responder by carotid US which was diagnosed by the reference standard.

Assessment of Bias and Evaluation of Evidence Quality.
Te quality of the studies included in the review was assessed using the QUADAS-2 [18]; this was independently undertaken by two authors (SW and AL) with disagreements (12%) settled by consensus.Te overall certainty was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations guidelines [19,20].Overall certainty in the pooled sensitivity and specifcity were categorised as high, moderate, low, or very low using the GRADEpro guideline development tool [21].

Statistical Analysis.
Te statistical analysis was undertaken using STATA 17.0 (StataCorp LLP, U.S.).Pooled sensitivity and specifcity were calculated for each carotid measure.In instances where the TP, TN, FP, or FN values were not published or available in supplemental data, these were calculated using a 2-way contingency table analysis [22].Meta-analysis was conducted in line with current standards [23] and side-by-side forest plots were used to examine variability between studies.Te hierarchical summary receiver operator characteristic curve (HSROC) was plotted for carotid US measures in cases where fve or more cohorts were available for analysis.Te following values were pooled using a bivariate random efects model: sensitivity, specifcity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (DOR).Heterogeneity was also examined using the I 2 statistic (whereby ≧75% suggested signifcant statistical heterogeneity between studies) in complement with inspection of forest plots and the HSROC models where applicable.Te contribution of threshold efect was evaluated by Spearman's coefcient (for which a value ≥ 0.6 suggested a threshold efect) and review of the HSROC model shape.Deek's funnel plot asymmetry test was used to assess for publication bias.A metaregression was utilized to assess subgroup bias; this could only be performed for pooled carotid US due to insufcient numbers within the subgroups.Metaregression was used to assess the efects of the following dichotomous variables: index test threshold (10% vs 15%), reference measurement ("gold standard"-LVOT VTI/PAC thermodilution vs. "non-gold standard"-pulse contour cardiac output (PiCCO), FloTrac ™ , noninvasive cardiac output monitor (NICOM)), type of fuid challenge (IV fuid vs. PLR), and severity of sepsis (septic shock vs. sepsis).

Study Selection and Study Characteristics.
Te study selection methodology is summarised in Figure 2. 7947 records were identifed from database and register searches, 3453 duplicates were removed, and 6 records excluded based on publication type.4568 records were Critical Care Research and Practice screened on title and abstract and 4501 excluded as irrelevant.67 full-text reports were retrieved, assessed for eligibility, and 51 reports were excluded.17 studies were included in the review and meta-analysis.In total, 860 patients underwent 1092 fuid challenges, of which 460 (42.1%) were fuid responsive.
Most studies had similar exclusion criteria (unable to tolerate PLR and carotid stenosis); however, some studies excluded common comorbidities which may have led to a skewed cohort.For example, Chowan et al. [26] excluded all patients with a body mass index (BMI) > 30 or if patients had any valvular heart disease or "cardiac stenosis."Another common issue was the lack of blinding between the index and the reference scans.No studies set a predetermined threshold for the index test which would be deemed as a "positive test;" these were all established post hoc.Te quality of the reference standard was generally high (Figure 3).Te GRADE evidence is provided in Table 3, and it found that for ∆CDPV and CBF had low accuracy for sensitivity and specifcity.
CBF demonstrated a pooled sensitivity of 0.70 (95% CI: 0.56-0.80),specifcity of 0.80 (95% CI: 0.50-0.94)(Figure 6(a)), and an AUROC of 0.77 (95% CI: 0.73-0.81)(Figure 6(b)).It had positive likelihood ratio of 2.00 (1.56 and 2.56) and negative likelihood ratio of 0.45 (0.34 and 0.60).Table 4 also shows data for the remaining carotid US measures, including pooled sensitivities, specifcities, positive likelihood ratios, and negative likelihood ratios.Unfortunately, ∆CAVTI and CFT did not have enough studies to perform a regression analysis; however, their pooled sensitivities and specifcities can be viewed in Table 5 and their paired forest plots in Figures 7 and 8. Given TAMEAN was only used in one study, no further analysis was performed.
Table 6 details the subgroup metaregression analysis performed.Taking a signifcant p value to be ≤ 0.05, several variables found signifcance.Specifcally, it was found that studies which used the reference gold standard measures (LVOT VTI and PAC) had signifcantly higher specifcities in detecting fuid responsiveness than studies which used less widely validated measures of CO.Passive leg raise had signifcantly higher specifcity than IV crystalloid, and studies which investigated sepsis/septic shock cohorts had a statistically signifcant higher sensitivity although this appears to be an insignifcant number practically with sensitivities only difering by 0.01.Table 6 shows data for each carotid US measure, including pooled sensitivities, specifcities, positive likelihood ratios, and negative likelihood ratios.
3.4.Heterogeneity.I 2 values for pooled sensitivity and specifcity were 48.6% and 68.0%, respectively.Tis indicates that there may be moderate to substantial heterogeneity between studies.Within the studies which examined, only ∆CAVTI and CBF heterogeneity was as

Discussion
Tis novel systematic review and meta-analysis reviewed the literature aiming to assess the diagnostic accuracy of carotid US in predicting fuid responsiveness in critically unwell patients.Seventeen studies were included in the review.We conclude that carotid US measures shows a moderate

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Critical Care Research and Practice sensitivity and a high specifcity in predicting fuid responsiveness in critically unwell patients.However, these results should be interpreted with caution due to the high heterogeneity among the existing studies and the low confdence in the accuracy fndings based on the GRADE assessment.
Previous reviews investigating carotid ultrasound in well patients and surgical patients have shown promising results, with pooled sensitivities of 0.83-0.85and specifcities of 0.86-0.89with a AUROC of 0.894-0.927for ∆CDPV in predicting fuid responsiveness [10,11].However, our review of critically unwell patient demonstrates that carotid US measures are less reliable in this population compared to these prior fndings.Notably, the sensitivity of ∆CDPV in our review was signifcantly lower at 0.72, indicating a decreased ability to accurately identify fuid responders among critically ill patients.Whilst specifcity of 0.87, the positive likelihood ratio of 5.48 and negative likelihood ratio of 0.31 for ∆CDPV were similar to previous reviews; the lower sensitivity represents a key diference in the diagnostic performance of carotid US in this specifc patient population.
In comparison to other ultrasound measures, carotid US was midrange in its ability to diagnose fuid responsiveness in critically unwell patients.Carotid US was signifcantly inferior to LVOT VTI which has sensitivity and specifcity of 0.88 and 0.95, respectively, in septic shock patients [41].It was also outperformed by internal jugular vein US in acutely unwell patients which had pooled sensitivities and specifcities of 0.82 and 0.78, respectively [42].It performed similarly in sensitivity to IVC diameter, 0.71, which was deemed unreliable as a measure of fuid responsiveness.Carotid US did have, however, a more favourable sensitivity to IVC diameter (0.71) [43].
Authors have hypothesized as to why carotid artery may be suboptimal when compared to the left ventricular outfow tract in acutely unwell patients.Tere has been a suggestion that the carotid artery may play an important part of cerebral blood fow autoregulation [44], meaning that changes in cardiac output are not accurately identifed at the level of the carotid artery.Tis efect may be further exacerbated in shocked and critically unwell patients refecting the decreased diagnostic utility of our review when compared to other measures of fuid responsiveness.
Most patient cohorts within this review were based in ICU.Tis in unsurprising as it has the highest density of hemodynamically unstable patients with clinicians having more time with the patient allowing serial carotid US measurements.Interestingly, the only emergency department study (McGregor et al. [34]) demonstrated the lowest sensitivity and specifcities among included studies, 0.45 and 0.46, respectively.Tis group of patients had received less intravenous fuid (compared to ICU patients); intuitively, this would suggest they would be more likely to be on the descending portion of the Frank-Starling curve and theoretically be more sensitive to fuid therapy when compared to ICU patients; however, this was not seen.Further studies are needed in emergency department settings to test carotid US diagnostic utility in this context.
A recent meta-analysis investigating factors afecting fuid responsiveness and how they are related to operative performance demonstrated that variables such as the volume  One of the most signifcant variabilities between the studies was the threshold which deemed a carotid US measure to be "fuid responsive."None of the studies set a predetermined value, rather the cutof was decided post hoc.Fluid responders according to the index test ranged from a 7% to a 23% increase, making it very difcult for   Critical Care Research and Practice clinicians to determine where fuid responsiveness lies with carotid US.Another area of variability between studies was the choice of reference standard.Most studies used either LVOT VTI or PAC to identify fuid responders, widely accepted as accurate ways of assessing cardiac output.
Girotto et al. [35] and Lu et al. [30] used PiCCO ™ which is a device that utilizes transpulmonary thermodilution.Several studies have shown PiCCO ™ to be reliable when compared to PAC [46,47].Jalil et al. [39] used FloTrac ™ which is a noninvasive device and has shown variable results in its ability to accurately identify changes in cardiac output.
Tree studies [28,29,39] used NiCOM, a noninvasive monitor which estimates cardiac output.Some studies showed that it can be a reliable measure [48], whilst others have shown that NiCOM cannot be used to estimate cardiac output, notably in critically ill patients [49].
4.1.Limitations.Tis study had several limitations.One limitation was that only two carotid US measures were amenable to meta-analysis.Unfortunately, CFT, ∆CAVTI, and carotid TAMEAN did not have enough data to perform the meta-analysis.Another limitation was the heterogeneity between the studies.Our analysis showed that there was a moderate interstudy heterogeneity.Te absence of a uniform cut-of for carotid US measures limits clinical applicability.
Tere is an opportunity for future research investigating the use of carotid ultrasound in hemodynamically unstable patients.
Prospective investigators should consider using ∆CDPV as their carotid ultrasound measure, in a homogeneous patient population (for example septic shock), with a predefned cutof for their carotid US measure.

Conclusion
We conclude that the available data from existing literature carotid US is moderately efective at diagnosing fuid responsiveness in critically unwell patients.However, our results suggest that carotid US is less accurate acutely unwell patients compared to surgical cohorts.Our study showed moderate to high heterogeneity within the literature and low accuracy confdence when applying the GRADE framework.Clinicians should use carotid US in critically unwell patients with caution.Despite the limitations, this systematic review and meta-analysis ofers the most rigorous and comprehensive evaluations of the existing literature.

Figure 4 (
b) shows a pooled AUROC of 0.81 (95% CI 0.78-0.85)and a HSROC model for pooled US measures.It had a positive likelihood ratio of 4.24 (2.49 and 7.23) and a negative likelihood ratio of 0.33 (0.25 and 0.43).

Figure 4 :
Figure 4: (a) Twin forest plots for pooled carotid US measures when assessing fuid responsiveness in hemodynamically unstable patients.(b) AUROC and HSROC model for pooled carotid US measures.

Table 1 :
Table 2 details the US equipment used for included studies.Characteristics of the included studies.

Table 2 :
US equipment for the included studies.
a several studies failed to identify the independence of the index test and reference standard, i.e., blinding.bTerecruitmentmethodology was not specifed in several studies.Some studies failed to exclude patients with conditions (aortic stenosis) where carotid US may be unreliable.cSomestudiesexcluded patients with heart failure and other comorbidities, which are common in critically unwell.Tis may impact its generalisability.Critical Care Research and Practice follows: ∆CAVTI I 2 values for sensitivity and specifcity were 35.6% and 59.7%, respectively, and CBF I 2 values for sensitivity and specifcity were 55.2% and 72.4%, respectively; this represents high heterogeneity.Figure9illustrates a statistically signifcant asymmetric Deek's funnel plot with a p value of 0.05, indicating high likelihood of publication bias.

Table 4 :
Diagnostic accuracy of carotid ultrasound measures to predict fuid responsiveness.

Table 5 :
Fluid responsiveness for included studies.

Table 6 :
Subgroup metaregression for pooled carotid US measures.
Gold standard � left ventricular outfow tract velocity time integral or pulmonary artery catheters, PLR � passive leg raise, CI � confdence interval.